On September 6, 2023, FDA announced its latest efforts to modernize the 510(k) process, outlining FDA’s latest improvements to strengthen the 510(k) Program and announcing release of three draft guidance documents.  This announcement addresses one of the commitments in FDA’s Medical Device Safety Action Plan: Protecting Patients, Promoting Public Health.

In the announcement, FDA highlights the Safety and Performance Based Pathway launched in 2019, which we blogged about here, noting that there are now ten device-specific final guidances allowing use of this pathway for clearance of the following device types:  Spinal Plating Systems, Orthopedic Non-Spinal Metallic Bone Screws and Washers, Magnetic Resonance Receive-Only Coils, Cutaneous Electrodes for Recording Purposes, Conventional Foley Catheters, Fracture Fixation Plates, Surgical Sutures, Denture Base Resin, Facet Screw Systems, and Soft (Hydrophilic) Daily Wear Contact Lenses.

The electronic Submission Template and Resource (eSTAR) program, which we blogged about here and here, also makes the highlight reel given its aim to improve consistency and efficiency in how 510(k)s are prepared.  Use of the eSTAR template for 510(k)s becomes mandatory on October 1, 2023 (unless exempt as described in the final guidance).

The biggest news in the announcement is the release of three draft guidance documents, which will be the subjects of future blog posts:

• Best Practices for Selecting a Predicate Device to Support a Premarket Notification [510(k)] Submission
• Recommendations for the Use of Clinical Data in Premarket Notification [510(k)] Submissions
• Evidentiary Expectations for 510(k) Implant Devices

Finally, the announcement notes that FDA will be engaging with manufacturers that are marketing pre-amendment status devices to ensure that the preamendment status for these devices is still applicable.  As a reminder, devices with preamendment status are those that were legally marketed in the US before May 28, 1976, have not been significantly changed since May 28, 1976, and for which a regulation requiring a premarket approval application has not been published.

Over the years, we’ve blogged on similar initiatives related to the 510(k) pathway.  In 2010, the 510(k) Working Group and the Task Force on the Utilization of Science in Regulatory Decision Making each released a preliminary report with a series of recommendations for the 510(k) program, including development of guidance and regulation to provide greater assurance that any comparison of a new device to a predicate is valid and well-reasoned (link).  In 2011, the Institute of Medicine released a report recommending elimination of the 510(k) process altogether (link), noting an inherent conflict between the legislative framework and FDA’s stated goals to protect patients and promote innovation in support of public health. In a statement released at the time, CDRH Director Jeffrey Shuren, M.D., J.D., stated, “We appreciate the IOM’s report on the 510(k) program. . . . FDA believes that the 510(k) process should not be eliminated but we are open to additional proposals and approaches for continued improvement of our device review programs.” More recently, in 2019, FDA announced a push for predicate modernization (link) following a 2018 plan to modernize the 510(k) program by eliminating use of old predicates, sunsetting older predicates, and establishing the Safety and Performance Based Pathway (link).

Even with the rapid evolution of medical device technology, FDA’s 510(k) program remains the most commonly used device premarket pathway, making the need for clarity of requirements and predictability in submission review essential for sponsors.   We look forward to a deeper dive into the new draft guidance documents for better understanding of FDA’s current thinking on these long-time challenges related to the 510(k) program.

CDER, CBER, and the Oncology Center of Excellence recently published a final guidance document titled “Considerations for the Use of Real-World Data and Real-World Evidence to Support Regulatory Decision-Making for Drug and Biological Products” as another part of its real-world evidence (“RWE”) Program.  This finalized a draft guidance issued in December 2021, largely similar in substance.

The focus of both documents is on non-interventional studies using real-world data (“RWD”).  Interventional studies are generally clinical investigations under the regulations and thus require an IND under 21 C.F.R. § 312.  In contrast, as the guidance explains,

a non-interventional study (also referred to as an observational study) is a type of study in which patients received the marketed drug of interest during routine medical practice and are not assigned to an intervention according to a protocol. Examples of non-interventional study designs include, but are not limited to, (1) observational cohort studies, in which patients are identified as belonging to a study group according to the drug or drugs received or not received during routine medical practice, and subsequent biomedical or health outcomes are identified and (2) case-control studies, in which patients are identified as belonging to a study group based on having or not having a health-related biomedical or behavioral outcome, and antecedent treatments received are identified.

Non-interventional studies thus do not require an IND.  Certain additional activities, such as questionnaires or laboratory tests, do not transform non-interventional studies to interventional.  In all cases, applicable requirements regarding informed consent (21 CFR Part 50) and Institutional Review Board review (21 CFR Part 56) must be met.

Even though an IND is not required, this guidance is intended to provide recommendations for sponsors to follow for using RWE from such studies for regulatory decision-making.  For example, as the guidance states, “FDA must be confident . . . that particular data sources or databases were not selected, or that specific analyses were not conducted, to favor a certain conclusion.”  The guidance describes steps sponsors should take to evaluate the study’s feasibility for such purposes.  It also encourages sponsors to post study protocols on a public website such as ClinicalTrials.gov.

The guidance also discusses ensuring that FDA has necessary access to the RWD, which requires sponsors ensuring that they are able to submit patient-level data for any clinical study included in a marketing application.  If certain RWD are owned and controlled by other entities, sponsors should have agreements with those entities to ensure such patient-level data can be provided to FDA and source data necessary to verify the RWD are made available for inspection as applicable.  The final guidance contains a new addition that states that if there is an appropriate justification as to why a sponsor cannot submit patient-level data to FDA through traditional channels, third parties can provide these data through either a pre-IND or Type V Drug Master File (“DMF”) and provide the sponsor with a letter of authorization for FDA to reference the data.  This appears to represent a measure of consideration for the difficulties sponsors can sometimes have gaining access to such data, which we discussed previously here.

Postmarketing safety reporting obligations apply, but, if the sponsor is using only a subset of a larger dataset to conduct its analysis, FDA does not expect the sponsor to search the entire dataset regarding all uses of the product for adverse events that would meet reporting requirements.  However, if the sponsor does become aware of adverse events that are subject to postmarketing reporting requirements during the course of the non-interventional study, such events must be reported in accordance with applicable requirements.

The guidance also describes study monitoring and other oversight responsibilities the sponsor should address, such as ensuring that there are adequate study records and that the study is conducted in accordance with the final protocol and SAP.

An interesting addition in the final guidance is that it explains that the topics discussed “apply to any type of RWD, including data on products used in clinical practice under an emergency use authorization (EUA).”  For obvious reasons, EUAs have been more prominent in recent years than they had been previously.  Even though the draft guidance was issued in 2021 after the onset of the COVID-19 pandemic, the Agency’s thinking now appears to be more reflective of this recent experience.

In a footnote, the guidance notes that RWD based on the use of products authorized under EUAs “can be used to generate RWE about the safety and/or effectiveness of that product.”  FDA has typically only discussed the use of RWE to support approval of a new indication for an already approved drug or to help support postapproval study requirements.  This is for obvious reasons and is also the statutory mandate under the 21^st Century Cures Act.  However, the inclusion of products authorized under an EUA would appear to mean FDA, at least in theory, is willing to accept RWE to support initial approval of products, because such products are not “approved.”  EUAs can, of course, be issued for new uses of approved products, but they do not have to be.  Does this offer the potential to use RWE for an initial approval?

The COVID-19 vaccines were initially authorized under EUAs, but their approvals do not appear to have been based on RWE.  For example, the Clinical Review Memo for Comirnaty states: “Post-authorization effectiveness data from observational studies . . . are limited to published literature and were not submitted as part of the licensure application. Therefore, FDA has not independently reviewed and confirmed the data or assessed the study designs for potential sources of bias.”  Similarly, the Integrated Review for Paxlovid states:

Since PAXLOVID was authorized for emergency use in December 2021, FDA has monitored the published literature on real-world evidence (RWE) studies that evaluated PAXLOVID effectiveness in outpatient COVID-19 populations. Most of the data sources used in these published RWE studies had insufficient longitudinal data and/or inappropriate study design to account for potential bias. Among the identified studies, five are based on appropriate source data and implemented design features that can account for the potential bias . . . . However, while the source data and certain design elements of these cohort studies were appropriate, there were insufficient details on the data source, methods, or analytical approach for a complete review to determine the quality of the results of the studies.

Although RWE was not used for these approvals, it does appear that FDA was open to such an approach if the data were fit-for-purpose.  Will it ever happen?  We will have to see – perhaps, with the help of this guidance, it will!

A drug manufacturer’s bad post-inspection grade from the U.S. Food and Drug Administration – labeled an “Official Action Indicated” classification – is generally devastating for the facility, not least because it can stall FDA approval of applications to market drugs manufactured at the facility.  Many of our clients have been confounded by their inability to secure a change in the classification of the facility, or to convince FDA to meet with representatives of the owner of the facility to explain what else they need to do.

As predicted in an earlier blogpost, FDA last week released a draft guidance that provides a pathway for generic drug manufacturers to secure a meeting with FDA so that affected companies can get answers to their questions in these circumstances.  The Guidance also commits FDA to some deadlines for when requests to meet will be accepted or denied, and for when meetings will be held if granted.  “Commits” is probably not the right word, although it is a term repeated frequently in the Guidance, since the Guidance at this point is only a draft, and, like other FDA guidances, it states in a highlighted warning that it “does not establish any rights for any person and is not binding on FDA or the public.”

Still, the document provides some guidance (naturally) as to materials required to submit a successful meeting request.  And the Guidance may be used as leverage to secure action from FDA on a meeting request.  We are not aware of a similar guidance for meeting requests from manufacturers of NDA drugs.  There is a discussion of the possibility of a post-Warning Letter meeting mentioned in FDA’s Regulatory Procedures Manual, but that discussion, which is not limited to generic drug manufacturers, seems to contemplate that it is FDA, not the Warning Letter recipient, that requests the meeting (”Program offices and centers also have the option of conducting a meeting with firm’s management prior to pursuing an administrative or regulatory action”).

The Guidance which is the subject of this blogpost specifically provides that it is applicable to facilities which manufacture either generic drugs or active pharmaceutical ingredients for generic drugs.

The Guidance sets three predictable conditions for application of the Guidance: the affected facility must carry an OAI classification; the facility must have paid the GDUFA annual facility fee or be named in a pending Abbreviated New Drug Approval application (an application for approval of a generic drug), and the Warning Letter that the facility seeks to close out must address only violations of or deviations from section 501 of the Federal Food, Drug, and Cosmetic Act (generally, these will be FDA observations related to failure to comply with Good Manufacturing Practice regulations).  The Guidance advises that the meeting request not be submitted until “significant progress” toward remediation has been made.

To request a meeting, the facility must submit a meeting package with specified information about the facility; information about the suggested meeting; a list of topics requested to be addressed during the meeting; and, perhaps most critically, information about corrective actions that have been taken or are in progress to address the deviations.  The Guidance states that any supplementary materials about “remediation progress” must be submitted at least 60 days before the meeting (footnote 23), and, somewhat inconsistently, that meeting “materials should be submitted to FDA 30 calendar days prior to the scheduled meeting date” (Section IX), “or else,” as an angry parent might scold a recalcitrant child.

As to FDA commitments, the Agency, in the Guidance, states it has committed to grant, deny, or defer the meeting within 30 days of the request at least 50 percent of the time in the current fiscal year, 70 percent of the time in the next fiscal year, and 80 percent of the time thereafter.  For the remaining meeting requests, there is no goal, so FDA can respond outside of the 30-day window.

Generally, FDA anticipates that the meetings will occur “6 months or later” after the facility submits its initial response to a Warning Letter.

And, after all that, many companies may simply get a response from FDA that a decision on whether a meeting will be scheduled is deferred, pending a reinspection.  Which can take months, or even years, for FDA to schedule.

Scheduling Criteria Under the Controlled Substances Act (“CSA”)

Schedule I:
• High potential for abuse;
• No currently accepted medical use in treatment in the U.S.; and
• Lack of accepted safety for use under medical supervision.  21 U.S.C. § 812(b)(1).

Schedule III:
• Potential for abuse less than drugs or substances in schedules I and II;
• Currently accepted medical use in treatment in the U.S.; and
• Abuse may lead to moderate or low physical dependence or high psychological dependence.  Id. § 812(b)(3).

****

Last October President Joe Biden asked the Secretary of the Department of Health and Human Services (“HHS”) and the Attorney General to “initiate the administrative process to review expeditiously how marijuana is scheduled under federal law.”  Statement from President Biden on Marijuana Reform, White House (Oct. 6, 2022).  Media outlets report, and HHS and Drug Enforcement Administration (“DEA”) officials confirm, that HHS has recommended rescheduling cannabis from schedule I to schedule III.  Bloomberg News reports that the National Institute on Drug Abuse agreed with the recommendation.  Riley Griffin, et al., US Health Officials Urge Moving Pot to Lower-Risk Tier, Bloomberg News (Aug. 30, 2023).

By recommending that DEA reschedule cannabis in schedule III, HHS has determined that cannabis does not meet schedule I nor schedule II criteria under the CSA.

HHS’ recommendation that DEA move cannabis to schedule III falls short of recommending total decontrol as many pro-cannabis advocates had hoped.  If DEA reschedules cannabis to schedule III, federal law will more closely align with that of the thirty-eight states that currently allow for some form of cannabis for medical use but would still conflict with the law of the twenty-three states where cannabis is legal for recreational use.

Cannabis in schedule III would require a prescription issued by a DEA-registered, state-licensed practitioner.  Legitimate handlers in the cultivation, manufacturing and distribution chain would have to obtain registrations with DEA.  Registrants would have to create and maintain inventory and transaction records, file certain reports and maintain adequate security.  Schedule III placement would loosen registration requirements for researchers.

Bloomberg News reports that it had seen HHS’ August 29^th letter stating that “FDA considered eight factors that determine the control status of a substance and recommended that marijuana be placed in the Schedule III category.”  Bloomberg News.  We surmise that the letter reviewed by Bloomberg News may have been the cover letter of HHS’ actual recommendation to DEA.

While HHS’ recommendation to move cannabis to schedule III delights some and disappoints others, it leads us to question how the agency arrived at its determination.  DEA and HHS last considered rescheduling cannabis in 2016.  DEA concluded, based on HHS’ evaluation, that there was “no substantial evidence that marijuana should be removed from Schedule I.”  Denial of Petition to Initiate Proceedings to Reschedule Marijuana, 81 Fed. Reg. 53,688 (Aug. 12, 2016); Denial of Petition to Initiate Proceedings to Reschedule Marijuana, 81 Fed. Reg. 53,767 (Aug. 12, 2016).

The CSA authorizes the Attorney General to schedule, reschedule or deschedule (decontrol) drugs or other substances after requesting a scientific and medical evaluation with scheduling recommendation from HHS.  21 U.S.C. § 811(b).  HHS’ recommendations are binding on DEA as to scientific and medical matters.  Id.  The scheduling analysis, commonly known as the “eight factor” analysis includes:

1. The drug’s actual or relative potential for abuse;
2. The scientific evidence of the drug’s pharmacologic effect, if known;
3. The state of current knowledge regarding the drug;
4. The drug’s history and current pattern of abuse;
5. The scope, duration, and significance of abuse;
6. The risk, if any, to public health;
7. The drug’s psychic or physiological dependence liability; and
8. Whether the drug is an immediate precursor of a controlled substance. § 811(c).

The 2016 review concluding that cannabis remain in schedule I was dependent on several factors.  DEA asserted that cannabis could only be rescheduled to schedule II in order for the U.S. to comply with its international treaty obligations.  Denial of Petitions at 53,688-89, 53,767-68.  The U.S. is still a signatory of the Single Convention on Narcotic Drugs, 1961, so we wonder how DEA might reschedule cannabis in any schedule other than schedule II.

While DEA made specific findings as to the eight factors in 2016, DEA also determined that rescheduling from schedule I to another schedule turned on whether cannabis had a currently accepted medical use in treatment in the U.S.  Id. at 53,689, 53,768.  Because HHS found that cannabis lacked an accepted medical use in treatment in the U.S., DEA had to deny the petitions to reschedule cannabis out of schedule I.

Why is HHS recommending rescheduling cannabis to schedule III now after concluding that there was no substantial evidence to move it from schedule I in 2016?  It is worth taking a closer look at the factors that led HHS and DEA to conclude that cannabis lacked a currently accepted medical use in 2016.

DEA and HHS agreed that a drug was considered to have a currently accepted medical use in treatment in the U.S. for purposes of the CSA if it was the subject of an approved new drug application (“NDA”) or abbreviated new drug application (“ANDA”) under the federal Food, Drug and Cosmetic Act (21 U.S.C. § 355).  Id. at 53,740, 53,821.  FDA had not approved an NDA or ANDA for cannabis for any indication in 2016.  Id.  FDA did approve Epidiolex, a cannabidiol oral solution derived from cannabis, in June 2018.  FDA Approves First Drug Comprised of an Active Ingredient Derived from Marijuana to Treat Rare, Severe Forms of Epilepsy, FDA News Release (June 25, 2018).  (DEA initially placed Epidiolex in schedule V, then later decontrolled it).  Does HHS consider Epidiolex approved for cannabis rescheduling purposes?

Lacking an approved NDA or ANDA, DEA established a five-part test in 1992 to determine whether a drug had a currently accepted medical use in the U.S.  Id. at 53,740, 53,7821; Marijuana Scheduling Petition; Denial of Petition; Remand, 57 Fed. Reg. 10,499, 10,504-06 (Mar. 26, 1992).  Under the test, a drug is considered to have a currently accepted medical use only if it meets all five elements.  Denial of Petitions at 53,740, 53,821.  Those elements are:

1. The drug’s chemistry is known and reproducible;
2. There are adequate safety studies;
3. There are adequate and well-controlled studies proving efficacy;
4. The drug is accepted by qualified experts; and
5. The scientific evidence is widely available. Id.

DEA reviewed these five elements in 2016 and found that cannabis did not meet the alternative test establishing a currently accepted medical use in treatment in the U.S.  DEA found under element 1 that chemical constituents including delta-9 tetrahydrocannabinol (“THC”) and other cannabinoids varied significantly in different cannabis strains, concluding that chemical composition among different cannabis samples was not reproducible. Id. at 53,761, 53,840.  DEA noted, however, that chemistry may be consistent enough to derive standardized doses if a specific cannabis strain is processed under controlled conditions.  Id.  DEA found that there were no adequate safety studies on cannabis use in specific, recognized medical conditions, nor were there adequate, well-controlled studies determining efficacy.  Id.  In addition, there was no consensus of experts opinion about the medical utility of cannabis treating specific recognized disorders.  Id.  DEA stated that there was a lack of currently available data on cannabis that sufficiently addressed its chemistry, pharmacology, toxicology, and effectiveness.  Id.  DEA noted there was a lack of scientific evidence about cannabis’ chemistry to a specific strain that could be formulated into standardized and reproducible doses.  Id.  Applying the five-part test in 2016, DEA found that cannabis met none of the five elements.

We also note that as a schedule I substance, cannabis’ potential for abuse was “high” in 2016 and wonder how its potential for abuse is now “less than drugs or [other] substances in schedules I and II” as required by a schedule III recommendation.  And how is cannabis now safe to use when there was “a lack of accepted safety for use . . . under medical supervision” seven years ago?

We are certainly curious whether DEA will reschedule cannabis, and if so, in which schedule.  In the meantime, we wonder how HHS arrived at its current recommendation.

Following up on our first post discussing Digital Health Technologies (DHTs) (here), this post will focus on development and qualification of DHTs for use in clinical trials for drug development.  Earlier this year, FDA hosted a public meeting, Understanding Priorities for the Use of Digital Health Technologies to Support Clinical Trials for Drug Development and Review, intended to bring together key stakeholders, such as patients, biopharmaceutical companies, DHT companies, clinicians, and academics, to understand the priorities for the development of DHTs for use in clinical trials.

Verification and validation of DHTs for use in clinical trials were topics on the minds of many, based on the questions raised by participants during the public meeting.   The draft guidance Digital Health Technologies for Remote Data Acquisition in Clinical Investigations (which we previously blogged on here) includes information on selection, verification, validation, and usability of DHTs and was referenced frequently in responses to participant questions.

It was noted that while there is a goal for consumer level usability, a lot is riding on the data generated by these devices, so there is also a need for rigorous development and validation of DHTs.  At the same time, it was noted that a perspective similar to CDRH’s approach to software as a medical device (SaMD) is desired, so that some of the verification can be done at the sensor level and used across studies, and tools for clinical care and clinical trials can have similar standards for data quality.

Considerations for verification and validation that were discussed included the level of accuracy needed between the DHT and the “gold standard,” as well as sources of variability.  It was also emphasized that DHTs need to be validated in the context of their use and be shown to be fit for purpose.  For example, studies using actigraphy in various disease areas, including Parkinson’s Disease, Atopic Dermatitis, and Heart Failure, were discussed and it was apparent that, while the underlying sensors may be similar, the specific information to be evaluated would vary and, therefore, validation in each population would be important.  It was also noted that validation studies should include normal participants as there is not extensive historical data on what “normal” looks like, given that the use of DHTs in studies is still relatively new.

As many individuals are already users of wearables and have mobile devices, there is a desire from the patient perspective to be able to use their own devices, which they are comfortable using, and to avoid the hassle of having two devices throughout a trial.  While desirable for patients, validation on multiple platforms can lead to challenges.  Identification of technical specifications for underlying hardware or a “white list” of hardware specifications may be an approach that could demonstrate interoperability between DHTs and hardware, allowing a bring-your-own option for some clinical trials. However, being fit for purpose must also be considered; while it might be acceptable to have multiple device types used for a natural history endpoint, studies using sensors to collect data for primary endpoints, e.g., for comparing drug A to B or placebo, may need more consistency to ensure data quality is sufficient for analysis.

If a DHT is a medical device, a common question is whether or not an IDE is needed to use the DHT in a clinical trial of a new drug.  FDA clarified that a medical device used as a DHT in a clinical study of a new drug would not need an IDE if is being used in accordance with its intended use, if its use is considered a non-significant risk, or if its use is considered a significant risk and necessary information to support the use is included in the IND.  It was noted that FDA’s digital health inbox (digitalhealth@fda.hhs.gov), managed by the Digital Health Center of Excellence, could be used to get questions answered on the regulatory status of a DHT used in a clinical trial.

Our takeaway from the public meeting with respect to development and qualification of DHTs for use in drug and biologic clinical trials is to carefully consider the patient’s perspective in light of the requirements for the DHT that are related to the study design and the data to be collected.  A systematic approach similar to that used in development of SaMD (including, for example, design controls) is recommended.

On Friday, August 25, 2023, FDA released a much-anticipated Final Guidance titled, “Enhanced Drug Distribution Security Requirements Under Section 582(g)(1) of the Federal Food, Drug, and Cosmetic Act,” addressing FDA’s implementation of certain electronic interoperability provisions of the Drug Supply Chain Security Act (DSCSA), which were due to become effective on November 27, 2023.   As industry is well aware, by the terms of the statute, the DSCSA’s interoperability provisions become effective ten years after its 2013 enactment, or on November 27, 2023.

The Guidance specifically states that it is issuing the Guidance – applicable to trading partners including manufacturers, distributors, dispensers, and repackagers – to address industry “readiness” to comply with the DSCSA’s provisions.

The compliance policies described in the Guidance focus on the requirement that, beginning November 27, 2023, all trading partners generally will be required to use electronic-based approaches to meet the enhanced drug distribution security requirements set forth in in FDCA section 582(g)(1) (Enhanced Drug Distribution Security).  As a reminder (as summarized in FDA’s Guidance) by November 27, 2023, trading partners will be required to:

• Use secure, interoperable, electronic approaches to exchange transaction information, which must include package-level product identifiers, and to exchange transaction statements;
• Have systems and processes in place to verify products at the package level;
• Have systems and processes in place to promptly respond with transaction information/statement for a product, if requested by FDA or other appropriate Federal or State official in the event of a recall or for suspect or illegitimate product investigations;
• Have systems and processes in place to securely facilitate the gathering of information needed to produce the transaction information/statement for a product going back to the manufacturer, as applicable, if requested by FDA, appropriate Federal or State officials (in the event of a recall or for suspect or illegitimate product investigations), or an authorized trading partner for purposes of investigating a suspect product or assisting with such a governmental request; and
• Have systems and processes in place to accept saleable returns under appropriate conditions (i.e., the ability to associate the saleable return product with the transaction information/statement with the particular product).

Drug manufacturers have had electronic systems in place since 2017.  However, FDA recognizes that some “technical and operational issues,” including those involving downstream trading partners and other “affected stakeholders,” may not be fully resolved by the deadline. The Agency also understands that additional time may be needed for systems to stabilize and be fully interoperable for accurate, secure, and timely electronic data exchange.  FDA intends the Guidance to provide “clarity and flexibility” to trading partners to “help ensure continued patient access to prescription drugs as the supply chain transitions to the interoperable, electronic product tracing at the package level under the DSCSA” while supporting “continued availability of products to patients.”  Guidance at 4.

So what is FDA going to do? 

FDA will exercise enforcement discretion concerning the implementation of the electronic interoperable exchange of information between trading partners to the package level.   FDA does not intend to take action to enforce the requirements, as described below, until November 27, 2024.   

More specifically,

• FDCA Section 582(g)(1)(B) requires that, as of November 27, 2023, the transaction information required to be exchanged include the product identifier (i.e., the standardized numerical identifier consisting of the NDC and serial number, lot number, and expiration date) at the package level for each package included in the transaction.
  • FDA does not intend to take action to enforce this requirement with respect to product introduced in a transaction into commerce by the product’s manufacturer or repackager before November 27, 2024, and for subsequent transactions of such product through the product’s expiry.
  • MOST IMPORTANTLY, FDA states this means that FDA does not intend to take action if the transaction information for product introduced in a transaction into commerce by the product’s manufacturer or repackager before November 27, 2024, does not incorporate—at the package level for each package in the transaction—the product identifier. FDA states this will “facilitate the use and exhaustion of product supply already in the supply chain prior to November 27, 2024.”  Guidance at 5.
• FDCA Section 582(g)(1)(D) requires trading partners to have in place processes and systems to respond promptly to a request for transaction information for a product in the event of a recall or an investigation of a suspect or illegitimate product.
• FDCA Section 582(g)(1)(E) requires systems and process to facilitate the secure gathering transaction information for each transaction in the event of a recall or investigation of a suspect or illegitimate product. FDA recommends that trading partners respond to such requests “with its relevant transaction information— if it directly transacted the product(s) that are subject to the request.”   Guidance at 7.
• FDCA Section 582(g)(1)(F) requires that each person accepting a saleable return have systems and processes in place to allow acceptance of such product, and may accept saleable returns only if such person can associate the saleable return product with the product’s transaction information and transaction statement.

Last but not least,  FDA emphasizes:

This guidance is not intended to provide, and should not be viewed as providing, a justification for delaying efforts by trading partners to implement the enhanced drug distribution security requirements under section 582(g)(1) of the FD&C Act. FDA strongly urges trading partners to continue their efforts to implement necessary measures to satisfy these enhanced drug distribution security requirements.

Guidance at 5.

FDA implores industry to diligently “keep at it.”  But in the meantime, enforcement activity with respect to the areas described above neither lingers nor looms in the imminent future.  We applaud FDA’s flexibility as industry seeks to comply with the DSCSA’s multiple requirements.

Hyman, Phelps & McNamara, P.C. (“HP&M”) is is proud to announce that 14 of the Firm’s attorneys have been selected to the 2024 edition of The Best Lawyers in America®.  Newly recognized this year are attorneys Josephine M. Torrente (FDA Law), Michelle L. Butler (FDA Law), Sara W. Koblitz (FDA Law), Allyson B. Mullen (FDA Law), and Anne K. Walsh (FDA Law), as well as McKenzie E. Cato, Kalie E. Richardson, and James E. Valentine, who have been named to the “Best Lawyers: Ones to Watch” list for Administrative/Regulatory Law, Health Care Law, and Health Care Law, respectively.

The other recognized attorneys, who are repeat selections to the list, include:

• Paul M. Hyman – FDA Law
• Ricardo Carvajal – Food and Beverage Law
• Robert A. Dormer – FDA Law
• Douglas B. Farquhar – FDA Law
• Jeffrey N. Gibbs – FDA Law
• Kurt R. Karst – FDA Law

The Best Lawyers in America® publication is based entirely on annual peer-review and has earned the respect of the profession, the media, and the public as the most reliable, unbiased source of legal referrals.  Recognition by The Best Lawyers in America® is widely regarded by both clients and legal professionals as a significant honor conferred on a lawyer by his or her peers.

As part of FDA’s Prescription Drug User Fee Act (PDUFA) VII goals published in PDUFA Reauthorization Performance Goals and Procedures Fiscal Years 2023 through 2027 (PDUFA Goal Letter), which we blogged about here, FDA included a goal for enhancing use of digital health technologies (DHT) to support drug development and review.  A DHT is considered “a system that uses computing platforms, connectivity, software, and sensors for healthcare and related uses.” DHTs have been used in clinical trials for decades in the context of measurements made when participants visit clinical trial sites.  More recently, use of wearable sensors and applications running on mobile devices (Apps) by study participants has introduced new questions on how to incorporate DHTs into the study, and what information is needed to verify and validate that they are fit for purpose in the study.

This blog provides an update on the DHT-related PDUFA VII goals that were targeted for completion in the first two quarters of FDA’s Fiscal Year (FY) 2023, including:

• By the end of Q2 FY 2023, FDA will establish a DHT framework document to guide the use of DHT-derived data in regulatory decision-makings for drugs and biological products.
• By the end of Q2 FY 2023, FDA will establish a committee including members from CDER and CBER to support implementation of the commitments in this section.
• By the end of Q2 FY 2023, FDA will convene the first of a series of 5 public meetings or workshops with key stakeholders including patients, biopharmaceutical companies, DHT companies, and academia to gather input into issues related to the use of DHTs in regulatory decision-making.
• By the end of Q1 FY 2023, FDA will publish draft, revised, or final guidance on the use of DHTs in traditional and decentralized clinical trials, addressing the validation of measurements made by DHTs, the development of novel endpoints using DHTs, the use of DHTs as new ways to measure existing endpoints, approaches to using the patients’ own DHTs such as cell phones or smart watches, usability considerations for patients, detection of safety signals during continuous data acquisition, and issues related to security and confidentiality of data.
• By end of Q2 FY 2023, FDA will enhance its internal systems to support review of DHT-related submissions including capturing key information about clinical trials utilizing DHTs to support tracking the number and rate of change of DHT related submissions.

FDA has made good progress on these initial goals, providing updates on the first four on the Digital Health Technologies (DHTs) for Drug Development website.  Earlier this year, FDA published the Framework for the Use of Digital Health Technologies in Drug and Biological Product Development (DHT Framework).  As part of the DHT Framework, a DHT Steering Committee has also been established.  In March of this year, FDA convened the first public meeting, Understanding Priorities for the Use of Digital Health Technologies to Support Clinical Trials for Drug Development and Review.  FDA also released, in December 2021, draft guidance for Digital Health Technologies for Remote Data Acquisition in Clinical Investigations.

The DHT Framework describes activities being implemented to meet the goals established in the PDUFA Goal Letter.  Activities within FDA include the establishment of the steering committee, enhancing the agency’s technical expertise and training, promoting consistency of evaluations across review divisions, statistical considerations in the analysis of DHT-derived data, and enhancing IT capabilities to support the review of DHT-generated data.  External programs include FDA meetings with sponsors, drug development tool qualification, establishing guidance, public meetings, demonstration projects, and engagement with external organizations.

The DHT steering committee includes senior staff from CDER, CBER, CDRH, including the Digital Health Center of Excellence (DHCoE), the Oncology Center of Excellence, and the Office of Clinical Policy and Programs.  Given that the same DHT measurement may be used for development of multiple drug, biologic, or medical device products and may itself be considered a medical device, the cross-center membership of the steering committee is intended to lead to consistent expectations for use of DHTs in product development and use of DHT-derived data in regulatory decision-making across the Agency.

We’ll continue to monitor FDA’s progress against its goals related to DHTs and the various activities outlined in the DHT Framework.

OPDP is coming out!  On the heels of a nuanced and more complicated Warning Letter addressing CFL claims and statistical presentations comes a new Untitled Letter from OPDP going back to its roots!  This most recent Untitled Letter to Exeltis alleges omission of risk information as well as misleading efficacy information in a promotional social media post and Exeltis’s failure to submit on 2253.  Honestly, the most surprising thing about this letter was its timing – issued only a week after OPDP’s first Warning Letter in well over a year making this newest Untitled Letter OPDP’s third letter in just over two months after a year hiatus.

So, what gives?

The letter itself is pretty typical of what we would expect to see from OPDP – prioritizing a communication that includes no safety information despite numerous efficacy claims, calling out an efficacy claim as misleading, and failing to submit promotional material on Form 2253.  Top it all off with an underlying promotional piece that is a sponsored social media post and we have lots of things that could be triggers for an OPDP Untitled Letter.

But… it’s the failure to submit on Form 2253 that’s giving this blogger trade complaint vibes.   And quite frankly, I think that’s the most interesting part of the story (please indulge some completely speculative musings here).

In January this year, six months after the last enforcement letter from OPDP, we blogged on a decision from the National Advertising Division (NAD) about misleading claims made in Rx drug promotion.  At the time, we spoke with Laura Brett, Vice President and New York Office Leader at BBB National Programs who confirmed that NAD has always been able to review prescription pharmaceutical claims, even if it has been underutilized in doing so.  NAD appeared to be inviting pharmaceutical companies to leverage its processes and submit complaints.  We speculated that, “[g]iven the drop in OPDP enforcement letters, NAD may represent a new venue for industry looking to challenge competitor Rx drug DTC advertising claims.”

A few months later there was more NAD news on the Rx drug promotion front: ViiV Healthcare, the subject of a competitor complaint submitted to NAD, declined to participate in NAD’s self-regulatory process as, according to NAD, ViiV indicated that “FDA is best positioned to assess the appropriateness of these prescription drug claims.”  The trade press was reporting that ViiV told NAD it provided FDA with notice of its claims, it had submitted promotional materials to FDA, and implemented FDA comments in its promotion.   Wow.  That news certainly took the NAD option down a few notches for industry in terms of alternative approaches for trade complaints.

Six weeks after the NAD/ViiV brouhaha, and about a year since its last letter, OPDP issued its first letter of 2023, citing misleading claims about efficacy and risk.  While not raising too many eyebrows given the subject matter, the letter appears to have opened the proverbial floodgates given that we now have 3 OPDP letters in a span of just over 2 months.  And, with my confusion over the “priority” of issuing a Warning Letter to AstraZeneca for its page 7 presentation in a 12-page healthcare professional brochure, after this newest letter, I couldn’t help but wonder [insert Carrie Bradshaw gif here – lol] whether these letters may share another common priority stated by FDA – the drugs were cited in complaints to the agency.  Did OPDP just stumble across Exeltis’s Facebook post for Slynd (it wasn’t submitted via Form 2253)?  Did OPDP just randomly check a 2253 submission of a 12-page healthcare professional brochure to find the promotion cited in its recent Warning Letter?  Can we expect more enforcement from OPDP in 2023 in response to trade complaints?

These are just some of the questions from this blogger.  Maybe industry doesn’t need NAD after all – maybe OPDP is “back.”

Last week the U.S. Attorney’s Office for the Western District of Texas announced that People’s Rx, a local chain operating five retail pharmacies and a compounding laboratory in the Austin area, agreed to pay $200,000 to settle allegations that it violated the Controlled Substances Act (“CSA”).  Austin Pharmacy to Pay $200,000 in Civil Penalties for Alleged Violations of the Controlled Substances Act, Aug. 16, 2023 (DOJ Press Release).  During a routine inspection in June 2022, Drug Enforcement Administration (“DEA”) diversion investigators determined that People’s Rx pharmacy violated recordkeeping requirements, improperly dispensed controlled substances to practitioners for office stock and issued prescriptions without authorization.  Id.  Investigators also found that the pharmacy sold pseudoephedrine (“PSE”) products but failed to self-certify in violation of the Combat Methamphetamine Act of 2005 (“CMEA”).  Id.

We note that in December 2020, the same U.S. Attorney’s Office announced that another pharmacy paid $320,000 to resolve allegations that in addition to violating recordkeeping provisions, it had also sold PSE and ephedrine products without self-certifying with DEA.  Odessa Pharmacy and Owner to Pay $320,000 in Civil Penalties for Alleged Violations of the Controlled Substances Act and the Combat Methamphetamine Epidemic Act of 2005, Dec. 2, 2020 (DOJ Press Release).

These settlements provide powerful reminders for “regulated sellers” of PSE, ephedrine and phenylpropanolamine.  “Regulated sellers” (retail distributors including pharmacies, grocery stores, general merchandise stores and mobile vendors) selling “scheduled listed chemical products” (“SCLPs”) (products containing ephedrine, PSE and phenylpropanolamine that may be marketed in the U.S. as non-prescription drugs) directly to walk-in customers or in face-to-face transactions by direct sales must self-certify with DEA that their employees have been trained on SCLP sales requirements.  21 U.S.C. § 830(e)(1)(B)(i).  Regulated sellers must renew their self-certification annually for each place of business where they sell SCLPs.  21 C.F.R. § 1314.40(b).  Mail-order distributors of SCLPs must also self-certify.  21 C.F.R. § 1314.102(a).

Regulated sellers must train employees responsible for delivering SCLPs into the custody of purchasers or who deal directly with purchasers by obtaining payment for the SCLPs then self-certify that they have done so.  21 U.S.C. § 830(e)(1)(A)(vii).

Regulated sellers must limit daily sales of SCLPs to 3.6 grams and 30-day limits to 9 grams, verify each customer’s identification, maintain records of each sale and keep products behind the counter or in a locked cabinet away from customer access.  Before they can sell SCLPs, regulated sellers must certify their employees have been trained on these requirements.  21 C.F.R. § 1314.35(a).  Certification must also include a statement that the regulated seller understands the requirements for selling SCLPs and will comply with those requirements.  21 C.F.R. § 1314.40(a).

Regulated sellers must train employees on SCLP sales requirement content developed by DEA and listed on the DEA website provided at the Diversion Control Division Retail Training Page.  DEA has developed two sets of training materials: one for regulated sellers who are not mobile retail vendors, and a second set for mobile retail vendors.

After employees have been trained, regulated sellers must self-certify through the DEA website provided at the Diversion Control Division Self-Certification Page.  Regulated sellers must print out and maintain a copy of their self-certification certificate.  In the unlikely event a regulated seller cannot recall whether they have self-certified, they can consult DEA’s monthly self-certification list of all who have current self-certifications found at the Diversion Control Division CMEA Monthly List.

Self-certification fees are waived for DEA-registered regulated sellers but the fee for initial self-certification and renewal for regulated sellers who are not DEA registrants is $21.00.  Id. at 21 C.F.R. §1314.42(a), (b).

I saw the sign…and the answer is no—FDA-approved labeling apparently is not enough under state failure-to-warn laws, according to certain courts.  While it has been long established that FDA-approved or mandated labeling preempts state failure-to-warn claims, some courts have decided that sometimes labeling just isn’t enough, never mind what FDA thinks.  FDA approves (or sometimes dictates depending on the product and regulatory pathway to market) the content of drug product labeling to set forth the conditions of use for which the benefits of the product outweigh the risks.  While the approval of that labeling is squarely on the shoulders of FDA, state failure-to-warn laws are used by plaintiffs to ask courts to pass judgment on the adequacy of labeling notwithstanding the fact that the scientific experts at the FDA have signed off on the labeling.  This begs the question of whether these courts, and other courts looking at other state law claims, are actually undermining FDA’s authority to determine whether a drug can be used safely and effectively under its proposed conditions of use.  After all, the labeling is intended to do exactly that: it informs patients and prescribers of the risks to ensure the product is used effectively and in a manner that mitigates risks, according to FDA’s understanding of the relevant science.

Brand drugs, generic drugs, and medical devices alike have all been the target of state failure-to-warn litigation; in a recent case, OTC acetaminophen is the target.  For OTC products, two pathways to marketing exist: through a full New Drug Application or Abbreviated New Drug Application, requiring FDA approval (including the approval of the label), or under an OTC monograph, which basically serves as an instruction manual for making and labeling certain OTC drugs.  Relevant to our conversation, OTC monographs establish conditions—such as active ingredients and indications for use, and product labeling—under which an OTC drug is generally recognized as safe and effective and does not require a product-specific approval.  Most OTC drugs, particularly drugs that have been around for a while, are primarily marketed pursuant to OTC monographs.  As explained in a 2020 CRS Report and a 2020 GAO Report, until the 2020 passage of the CARES Act (see our blog post here), amending a monograph was challenging because “the agency’s ability to update and finalize monographs in response to safety issues and to reflect new scientific information was limited by the rulemaking process the agency was required to follow, as well as insufficient resources. Agency officials estimated that it took at least 6 years to complete the required rulemaking process.”  More than a few have taken far longer—literally decades.  The GAO Report further explained that the agency did not have the resources to regulate the estimated 100,000 OTC drugs marketed through the monograph process.  (Recall that the funds provided under the Prescription Drug User Fee Acts (PDUFA) are not available to support the agency’s efforts related to monograph drugs.)  FDA did, however, try to identify safety issues through the medical literature and (after 2007 when mandatory safety reporting for OTC human drug products marketed without an approved application became effective) through the adverse event reporting system.  Further, FDA has utilized a variety of strategies to call attention to safety issues through Dear Doctor letters or other forms of communication, even if directing changes to labeling is difficult.  The passage of the OTC monograph provisions of the 2020 CARES Act was intended to address the lack of resources, and user fees are being collected, but, as expected, implementing all the other aspects of the new law is a long process.

FDA’s jurisdiction over OTC monograph drug labels is clear, but some courts seem to believe that compliance with the label requirements set forth in the relevant monograph is not only not sufficient, but also is discretionary, implicitly chipping away at the authority of the agency.  A recent state law failure-to-warn case in the SDNY makes that very point.  There, Plaintiffs (a mother individually and on behalf of her child) alleged that Defendants Johnson & Johnson and Walmart failed to include a warning on acetaminophen products they sold pursuant to the relevant OTC monograph, as well as under NDAs, that use of acetaminophen while pregnant causes children to be born with autism spectrum disorder and ADHD.  Plaintiffs also alleged strict liability for design defect due to inadequate warnings and precautions and negligence and breach of consumer protection laws.  Plaintiffs alleged that Defendants had a duty under state law to warn consumers of a (potential) risk of prenatal exposure to acetaminophen.  Interestingly, the Plaintiffs alleged that this duty existed when the mother was pregnant in 2015 even though the studies relied upon in the litigation are from 2021.  But we digress.

Defendants moved to dismiss on grounds that state failure-to-warn claims are preempted, as FDA approved the NDA-product labeling and dictated the labeling for OTC monograph products, but the Court disagreed.  It’s important to note here that the warnings and precautions listed in the acetaminophen labeling complied with FDA’s Pregnancy Rule (which applies to all OTC systemic products), stating “if pregnant or breast-feeding ask a health professional before use,” and with the acetaminophen OTC Monograph and the relevant NDAs.  Thus, Defendants argued that FDA already required the warning for pregnancy, rendering the decision to use it during pregnancy to a healthcare professional, and that FDA had considered the risks of in utero exposure and rejected the addition of those risks to the labeling.  Nevertheless, despite the immense hurdles to changing a warning in a monograph (as specifically noted in the GAO Report), despite that FDA expressly rejected the change to the monograph at the time the Plaintiff-mother was pregnant in 2015, and despite the clear and specific language of the Pregnancy Warning Rule, the Court denied the Motion to Dismiss, holding that the failure-to-warn claims were not preempted.

Though the case addressed both NDA and monograph OTC products, it is notable as one of the first to address the issue of preemption with respect to the Pregnancy Warning Rule or to OTC Monographs.  On these issues, the Court took the position that neither expressly forbade including additional labeling, and thus, under both of these FDA schemes, the presumption is that sponsors can add stronger warnings to product labeling without FDA concurrence; consequently, the Court concluded it was not impossible to follow federal law and provide appropriate warnings under state protection laws.  Specifically, the Court explained, because “[t]he Pregnancy Warning Regulation simply does not speak to whether a further warning related to a drug’s use during pregnancy can be added to the general Pregnancy Warning on a drug label, whether added by the FDA or added by a manufacturer,” the ”regulation does not, therefore, preempt state law . . . .”  Similarly, the Court stated, “FDA’s silence regarding acetaminophen-specific warning does not preempt state law.”  Thus, the Court presumed, there is no reason that the sponsors could not add stronger pregnancy warnings.

And, as the Supreme Court previously explained, the Court noted, if the Defendants could have unilaterally strengthened warnings on labeling without prior approval from FDA, state failure-to-warn claims are not preempted.  Here, the Court presumed that Defendants could do just that: absent an attempt by Defendants to change the labeling and subsequent FDA rejection, the Court decided that Defendants could have added truthful warnings about the risk of in utero exposure without violating federal law.  Indeed, the Court explained, it could hardly be otherwise, because if a sponsor is “not free to add truthful warnings related to the use of acetaminophen during pregnancy, then that would mean that all manufacturers of OTC monograph-approved drugs intended for systemic absorption would be similarly barred from adding to their labels truthful warnings about the use of their own drugs during pregnancy.”  But what the Court didn’t consider is that, if sponsors of OTC Monograph drugs could change their labeling to include more warnings without FDA buy-in, identical products could have very different labeling, which is not contemplated under the OTC Monograph scheme.  While OTC Monographs may no longer include exact wording requirements for some information, this is only because, as the Court reminds us, “there can be various ways of accurately stating the same thing;” the problem arises when there are substantive changes to the labeling, like the addition of new warnings, such that all OTC Monograph products for a given drug don’t actually state the same thing even when there is no actual difference in risk between the products.  This can lead to consumer confusion with consumers believing that there are actual differences.  This is precisely the type of confusion FDA strives to avoid.

The Court’s determination that, even though FDA fully dictated the labeling for OTC Monograph products, Defendants could lawfully change the labeling undermines both FDA’s attempt to ensure consistency in the OTC drug market, as well as FDA’s decision that a healthcare professional should be consulted before use of acetaminophen in pregnancy; instead, it places the onus on manufacturers to basically beg FDA to modify monographs.  This is because the presumption that manufacturers can unilaterally make substantive changes to the labeling of an OTC Monograph drug product is false.  Just like it was over a decade ago in Pliva v. Mensing in the case of generic drugs, where the Supreme Court held that failure-to-warn claims for generic drugs were preempted precisely because the Reference Listed Drug holder—and FDA—controlled whether the generic sponsors could add new warnings to the labeling; in other words, generic drug sponsors could not just change labeling to add new safety warnings.  And like the Court said in Pliva v. Mensing, “even if [the sponsors] had fulfilled [a] federal duty to ask for FDA assistance, they would not have satisfied the requirements of state law.”  That requirement would only be fulfilled if FDA agreed to such a change.  And indeed, after Pliva v. Mensing, there was much discussion about adding authority to the FDC Act to allow generics to make safety changes to product labeling without FDA approval.  FDA went so far as to issue a proposed rule (see our blog post here), that ultimately went nowhere.  And that such a proposal ultimately fizzled out is not surprising considering the issues with overwarning and the relatively limited profits made by generic companies when compared to the additional liability burden created by the obligation to make safety changes separately from the Reference Listed Drug product.  The same considerations ring true for OTC drugs.

FDA, for years, has been concerned with overwarning.  As FDA explained in a 2008 Rulemaking, FDA’s existing policies are “intended to ensure that scientifically valid and appropriately worded warnings will be provided in the approved labeling for medical products, and to prevent overwarning, which may deter appropriate use of medical products, or overshadow more important warnings.”  In the Proposed Rule, FDA explained further that “[e]xaggeration of risk, or inclusion of speculative or hypothetical risks, could discourage appropriate use of a beneficial drug, biologic, or medical device or decrease the usefulness and accessibility of important information by diluting or obscuring it. As FDA has stated, labeling that includes theoretical hazards not well-grounded in scientific evidence can cause meaningful risk information to lose its significance.”  In a 2017 Request for Information, the agency similarly noted that overwarning, or the concept that “individuals are exposed to so many warnings in the course of daily life that they are less likely to pay attention to any one particular warning,” “may lead consumers to discount all risks, or miss the most important risk information.”  OPDP therefore initiated a study of “how repetition and overwarning apply to the presentation of risks in promotional prescription drug print pieces.”

If those marketing OTC drugs under the monograph were required to add new warnings because some literature noted a risk, the chances of overwarning are high, rendering the existing risk information potentially less impactful. It also raises questions about how much medical literature is required before a new warning is required, does it matter where it comes from (reddit or NEJM), or what types or quality of evidence are presented, and what if other medical literature disagrees?  And, as in the acetaminophen case, what if FDA has already considered and rejected the need for a specific warning?

Notably, FDA had even addressed the strength of the evidence for acetaminophen warnings.  Rather than adding in every potential risk in the case of acetaminophen, in that 2015 Drug Safety Communication, FDA specifically recommended that pregnant women consult their doctors before taking acetaminophen:

Pregnant women should always consult with their health care professional before taking any prescription or OTC medicine.  Women taking pain medicines who are considering becoming pregnant should also consult with their health care professionals to discuss the risks and benefits of pain medicine use.  Health care professionals should continue to follow the recommendations in the drug labels when prescribing pain medicines to pregnant patients.

FDA, in other words, directed, and continues to direct, pregnant women to a learned intermediary.  According to FDA, therefore, use in pregnant women is neither condoned nor directed by the labeling—that’s a question for them to discuss with their doctors.  The Court acknowledged all this, but nonetheless found that the failure-to-warn claims were not preempted because, essentially, the Defendants should have at least tried to change the labeling.

Unlike prescription drugs with approved NDAs, OTC monograph drugs generally are not blockbuster drugs protected by patents for which sponsors expect huge returns.  FDA has estimated that there are more than 100,000 OTC drugs marketed through the monograph process, with 800 active ingredients for over 1,400 uses as of December 2019.  With all that competition, particularly with respect to drugs as well-known as acetaminophen, it’s unlikely that there’s a lot of money to be made by an individual company; while the acetaminophen market may be large, there are just so many market participants.  If every company that brings an OTC Monograph drug to market is hit with state failure-to-warn claims and forced to litigate such claims to completion, the market is sure to shrink.  For many brands, the potential return is too small when compared to the potential for immense products liability claims for labeling that the sponsor cannot even control.  Liability is precisely why the vaccine market shrunk so significantly in the 1980s, going from 26 manufacturers to 4, after lawsuits claiming $3.5 billion in damages were brought between 1980 and 1986.  Things got so bad that Congress acted to shield vaccine manufacturers from liability in order to ensure sufficient availability of vaccines.  There’s no reason to believe that continued state liability for FDA-mandated labeling would result in any different outcome where there is unfettered opportunity to bring state law claims against OTC monograph sponsors for labeling products in accordance with FDA requirements.

Nevertheless, court decisions that contrast with FDA’s positions are imposed on drug manufacturers of all sizes and types.  Take, for example, sunscreens.  In 2023, a Northern District of California Court determined that state law claims alleging violations of unfair competition and other consumer protection provisions could stand notwithstanding the fact that cosmetic foundation with sunscreen complied with FDA’s labeling requirements for sunscreens.  There, the Court let proceed Plaintiffs’ suit alleging that foundation including sunscreen, advertised with a 24- or 25-hour duration, misleadingly suggested that sun protection could last for 24 or 25 hours, even though the directions stated clearly and unambiguously—and compliant with FDA’s sunscreen labeling rules—that the product must be reapplied every 2 hours for sunscreen coverage.  Similarly, the District Court of Connecticut found that allegations of various state consumer protection laws for failure to list benzene as an ingredient in Banana Boat sunscreen were not preempted when nothing in FDA regulations suggests that benzene, as an impurity, is an “ingredient;” additional consumer protection claims about benzene also were not preempted because the Court found that nothing in the OTC sunscreen monograph precluded a warning about benzene.

To be fair, we note the many examples of cases where courts have found such claims preempted.  But cases like the ones described here create precedent for the next OTC monograph case.  In turn, each of these cases triggers concerns about how far courts are willing to go.

In January 2023, Vanda Pharmaceuticals, Inc. (Vanda) submitted two interesting and substantially similar citizen petitions (Docket Nos. FDA-2023-P-0313 and FDA-2023-P-0344) regarding its product Hetlioz (tasimelteon).  Vanda requested that FDA revoke the approval of Apotex’s and Teva’s generic versions of Hetlioz on the grounds that the generic tasimelteon products did not meet the statutory “same labeling” requirement for generic drugs found in 21 U.S.C. § 355(j)(2)(A)(v).  This statutory provision requires generic drugs to have the same labeling as that approved for the listed drug “except for changes required because of differences approved under a [suitability petition, allowing for certain differences] or because the new drug and the listed drug are produced or distributed by different manufacturers.”  FDA regulations, at 21 C.F.R. § 314.94(a)(8)(iv), interpret these provisions to also allow changes due to an aspect of labeling protected by patent or exclusivity.

The difference at issue here is the fact that Vanda’s Hetlioz product includes braille writing on its packaging, with some accompanying language (“Do not cover Braille”), and the generic products’ labeling does not.  This matters particularly strongly in this case, Vanda argued, because the generic products are approved for only one indication, a sleep disorder that disproportionately occurs in blind individuals.  Vanda’s Hetlioz was, in fact, the first FDA-approved drug product to include braille labeling.  Nor did this difference meet any of the statutory or regulatory exceptions to the “same labeling” requirement, Vanda argued.  As such, Vanda’s citizen petition stated that these approvals are “clearly erroneous under the FDCA and agency regulations and will put . . . patients in harm’s way.”  The citizen petition requested FDA revoke the approvals and recall the product in the marketplace.

FDA responded in late July, denying Vanda’s petitions.  FDA’s response stated that the two generic sponsors had submitted side-by-side comparisons of the labeling for their products as compared to the reference listed drug (RLD) Hetlioz, noting the differences Vanda raised in its petition.  FDA concluded at that time that these differences still met the “same labeling” requirement due to the “different manufacturer” exception.

FDA’s petition response included several grounds on which it based its decision to deny Vanda’s citizen petitions.  First, FDA noted that the Agency has interpreted the “different manufacturer” exception broadly, on a case-by-case basis, and listed various examples of when they have done this in the past.  Such differences have included different disposal methods in the labeling, a different ingredient safety warning, and a situation where a generic did not include halal and kosher certifications in its labeling where the RLD labeling did.  Other differences have included differences in font, color, trade name, and other trade dress.  Thus, FDA’s response argued that Vanda’s interpretation of the exception is inconsistent with FDA’s.

Secondly, FDA’s response stated that the only pieces of information that were repeated in braille in Vanda’s container labeling were the proprietary name and the strength of the drug product.  As the proprietary name is not generally included in generic drug labeling, which is interpreted as an acceptable difference, this leaves only the strength as the information that would be expected to appear in generic labeling.  FDA also disagreed that the inclusion of the strength or a product name was necessary for the safe and effective use of the drug product, noting that this was a voluntary addition to the labeling by Vanda, not required by the Agency during review.  FDA did request a Label Comprehension Study during Hetlioz’s review to evaluate whether the braille might introduce a new risk of medication errors, which Vanda conducted, but, the response stated that this does not establish that the braille is necessary for the safe and effective use of the product.

Moreover, other information, such as dosing instructions and warnings, were not presented in braille.  FDA argued that this rebutted Vanda’s argument regarding the necessity of the braille to the safe and effective use of the product.  FDA stated in its response that there is not sufficient support for a claim that the absence of braille will lead to medication errors for the patients at issue, nor have there been any such reported to date.

Finally, FDA’s response stated that the accompanying language (“Do not cover Braille”) would be acceptable to omit, given that it might cause confusion where there is no braille on the generic product labeling, and this would not violate the “same labeling” requirement.

Vanda has a history of challenging FDA statutory interpretations in court, so it’s possible this is not the last we hear of this issue.  However, we will have to wait and see what happens.

Well, if you, like many within industry, felt emboldened to disseminate promotional materials that may push the envelope on efficacy (so long as your risk information was tight) think again!  OPDP is back in the game, letting all the people know that they are back to run the show.

In what may be the surprise “Warning Letter of the Year” (can you tell this blogger was pretty shocked?) OPDP took issue with AstraZeneca’s professional sales aid for Breztri Aerosphere (budesonide, glycopyrrolate, and formoterol fumarate) inhalation aerosol for oral inhalation use.  Why is this Warning Letter so shocking?  Let’s take a walk down OPDP Warning Letter memory lane . . .

• The last Warning Letter OPDP issued was in early 2022 to CytoDyn for promoting its investigational drug as an effective treatment for COVID-19 despite a failed study (and despite an FDA release issued a year prior about the same failed study – but that’s another story).
• Prior to the CytoDyn letter in 2022, OPDP issued a Warning Letter in 2021 to CooperSurgical for a DTC video entitled “Paragard: Family Planning During the Pandemic” which failed to communicate ANY risk information.
• And before CooperSurgical, another 2021 Warning Letter was issued to AcelRx for the infamous “Tongue and Done” tagline used to promote a Schedule II controlled substance subject to a REMS program that requires a healthcare professional’s precise placement of the drug using a single-dose applicator into the patient’s sublingual space.

Whew!  Pretty egregious stuff, right?

In this most recent Warning Letter, however, OPDP did not take issue with ANY of the safety information presented about Breztri in the sales aid; rather, objections were focused solely on false or misleading claims related to efficacy.  And those efficacy presentations included disclaimers and context, yet FDA found they were insufficient to “mitigate the misleading impression” caused.  Sheesh!

Let’s go over some background information relating to Breztri and the OPDP Warning Letter.

Breztri was approved just over 3 years ago in July 2020 for the maintenance treatment of patients with chronic obstructive pulmonary disease (COPD).  The indication includes a limitation of use that Breztri is not indicated for the relief of acute bronchospasm or for the treatment of asthma.  The drug does not have a Boxed Warning, but has an extensive list of Warnings (17 in total).  The promotional piece at issue is a 12-page brochure intended for healthcare professionals, with the offending presentations appearing on pages 6 and 7.

OPDP first took issue with a headline and graph presented on page 7 of the 12-page brochure.  The headline, “Difference Observed in Time to All-Cause Mortality (Over 52 Weeks)” appears above a graph titled “Secondary Endpoint Study 1:  Time to all-cause mortality in the ITT population” and includes claims that there is an observed relative difference between Breztri v. LAMA/LABA.  The Kaplan Meier graph closely resembles one appearing in the American Journal of Respiratory and Critical Care Medicine Journal, a bi-weekly peer-reviewed medical journal published by the American Thoracic Society.  The page in the brochure calls out that the data were also included in the New England Journal of Medicine.  FDA took issue with the representation that there was a 49% observed relative difference in all cause mortality with Breztri v. LAMA/LABA because the results intended to support that claim come from a study with multiple secondary endpoints and there was a failure to show significance on endpoints ranked higher in the analysis hierarchy.  Despite AstraZeneca’s inclusion of the statement “These results are observational in nature, and any comparisons between treatment arms should be interpreted with caution,” FDA provided its typical response re disclaimer statements – that they do not “mitigate the misleading impression” of the presentation.

The second issue raised by OPDP was that the inclusion of a p value in conjunction with a claim suggested statistical significance when the results were not, in fact, statistically significant.  OPDP states that a p-value is generally understood to indicate statistical significance if it is less than 0.05.  However, in the testing strategy from the trial,

the raw p-value of each hypothesis test was compared to the corresponding critical value to determine whether the test was statistically significant.  As the p-value for the Breztri to ICS/LABA comparison (p=0.02) was greater than the critical value (0.008) for that hypothesis test, the result, per the threshold set by the testing strategy, is not statistically significant.  Therefore, the presentation of these claims (i.e., with a p-value of 0.02) creates the misleading impression that Breztri provides a statistically significant reduction in severe exacerbations compared to ICS/LABA by 20% when this has not been demonstrated.

FDA acknowledged a footnote that explained that the analysis was based on predefined Type-1 error control plan however, as above, FDA stated “this does not mitigate the misleading impression.”

What does this mean?

While one could argue that these presentations are misleading because they overstate the efficacy of Breztri, the presentations are limited to the middle of a 12-page brochure intended for healthcare professionals and the brochure otherwise describes the studies discussed and includes relevant safety information.  The claims are (presumably) not made to patients and each had context that described how the data was interpreted.  This certainly doesn’t seem like promotion that is prioritized for OPDP enforcement– while the drug has many warnings, it is not a Boxed Warning drug or an opioid, it is not subject to a REMS, nor is it used for COVID-19.  As Breztri has been approved for just over 3 years, this is not launch material for a newly approved drug, nor is it a product that has been the subject of previous compliance letters and the promotion is not a “far-reaching” campaign.

In a post-CFL world, these claims walk the line in that they could be “consistent” with the FDA-required labeling in accordance with FDA’s stated 3-factor analysis.  Clearly, OPDP thinks differently.  As part of the Warning Letter, OPDP states, “To date, no drug has been shown to improve ACM in COPD” and includes a footnote that states, “Through the issuance of this letter, FDA does not intend to convey any views on whether data that did show that Breztri improved ACM in COPD would support a change to the FDA-approved labeling for Breztri.”  This seems to suggest that FDA expects this type of outcome claim to be included in labeling.

Enforcement may also have been triggered by the manner of the presentation.  If AstraZeneca wanted to present this data in text form as opposed to colorful graphics, careful to equally present context with a description of the findings, this may not have resulted in a Warning Letter.

But a Warning Letter?  This blogger is curious to see what else OPDP has up its sleeve for 2023.  At a minimum, this letter gives industry a lot to think about as it considers Rx drug promotional materials.

Francis Godwin, Director of the Office of Manufacturing Quality of the Office of Compliance at FDA’s Center for Drug Evaluation and Research provided useful information (presentation attached here) Tuesday at the GMP by the Sea Conference.  He talked about regulatory discretion being exercised for drug manufacturing facilities with serious compliance problems, about how firms should respond to FDA inspectional observations, and about an upcoming guidance that will be of interest to generic drug manufacturing firms that have received Warning Letters.

First, Mr. Godwin provided updated information on the presentation made the day before by another CDER official, Jennifer Maguire, the Director of the Office of Quality Surveillance within the Office of Pharmaceutical Quality at CDER,.  We summarized in a blog post yesterday  her comments about facilities with FDA inspections that had been classified as Official Action Indicated, the most serious classification for FDA inspections relating to current Good Manufacturing Practice compliance.  Mr. Godwin’s presentation made the same point, although with more data to back it up: so far this fiscal year (since October 1, 2022), the number of OAI inspections resulting in the exercise of regulatory discretion is unusually high.  Regulatory discretion, in this context, means basically that FDA has decided not to issue a Warning Letter, request a Regulatory Meeting, impose an Import Alert, or to take a more serious enforcement action.  There were 286 FDA GMP-related inspections of drug manufacturing facilities in this period with OAI classifications.  Of that number, 80 of the facilities were graced with FDA’s regulatory discretion (28%), 75 resulted in imposition of an import alert (26%), 66 resulted in Warning Letters (23%), and 62 prompted Regulatory Meetings (22%).

Mr. Godwin confirmed that the percentage of OAI facilities receiving regulatory discretion was unusually high, and stated that he believes (as we posited in the blogpost yesterday) that the higher percentage was due to COVID-related causes: there were more facilities making critically needed drugs, and the drug supply chain has not recovered from COVID shutdowns and delays, making shortages of important drugs much more likely.  FDA would not want to curtail supplies of vitally needed drugs by, for example, imposing an Import Alert.

Second, Mr. Godwin said he reads numerous responses to FDA Forms 483, the report that FDA issues at the end of a GMP inspection, and that it is critically important that the responses include a narrative summary of the major remedial actions that a company has made or intends to make, and discuss if a company contests a finding.  “Document dumps,” he said, are not helpful without the assistance of a narrative placing the documents in context.

Third, Mr. Godwin said that he expects FDA to issue soon a Guidance document that will address how generic drug manufacturers should request, and what they should present, at meetings with his office that will be held after the company receives a Warning Letter.  After his remarks, Mr. Godwin stated that the Guidance, and the necessity of FDA providing such a meeting is one of the commitments in the GDUFA III  Commitment Letter.

At the GMP by the Sea Conference ongoing in Cambridge, Maryland, a presentation was made by a representative of FDA’s Center for Drug Evaluation and Research that shows some interesting trends in enforcement.

Jennifer Maguire, the Director of the Office of Quality Surveillance within the Office of Pharmaceutical Quality at CDER, told attendees that there were 163 FDA inspections from the beginning of October 2022 to the end of March 2023 conducted at drug manufacturing facilities (excluding drug compounding facilities) that were classified as Official Action Indicated (OAI).  OAI is FDA’s classification for facilities it deems to be in an unacceptable state of compliance.

Of those, only about a quarter (26%) resulted in Warning Letters, less than a quarter (19%) resulted in imposition of import alerts (restricting or prohibiting imports into the United States of drugs from a specified facility), slightly more (24%) resulted in regulatory meetings with the agency, and the plurality (29%) resulted in FDA exercising “regulatory discretion,” which means a decision not to take enforcement action.  One inspection resulted in FDA’s securing a consent decree to restrict or shut down operations, and two resulted in an “untitled letter,” which is not available to the public on FDA’s website.

The large percentage of OAI inspections resulting in the exercise of regulatory discretion is unusually high.  Lest we grow too optimistic, though, industry should be aware that this-larger-than-historical number of what is a favorable disposition may not be a trend that will continue.  It is believed that many of the inspections conducted during this period were of facilities producing essential medicines, such as COVID-related medications, for which FDA did not want to create or exacerbate product shortages.

Other interesting datapoints from her presentation:

For the period from FY2000 to May of 2023, the percentages of drug manufacturing inspections with OAI classifications was lower in China (about 5% of inspections) than in the United States (8%).  Again, this is a trend that may not continue: not many FDA inspections were conducted in China during this period due to COVID travel restrictions, whereas U.S. facility inspections are approaching traditional levels.

FDA has created a list of essential medicines, and provided calculations of how many of the drugs were totally or partially manufactured in countries other than the United States.  FDA also looked at how may of the Active Pharmaceutical Ingredients for those drugs were manufactured overseas.

• Remarkably, only 11% of the finished drug products were totally manufactured overseas, although 92% of the API for those drugs was either totally or partially manufactured in foreign countries.
• Of those facilities manufacturing essential medicines deemed to be the product of complex manufacturing processes, 68% were located in the U.S., the European Union, or the United Kingdom. For those facilities manufacturing essential medicines deemed to be non-complex, 60% were located in these countries.

These figures confirm that, although the vast percentage of active ingredients of important pharmaceuticals comes from overseas, the actual manufacturing of finished dosage form drugs occurs in the United States or Europe (broadly defined to include the UK).

The GMP by the Sea conference, an annual conference sponsored by PharmaConference.com, is an annual event in Cambridge, Maryland, linked here.